The present invention relates to an artificial lung surfactant having a surface activity similar to a natural lung surfactant and a remedy for respiratory distress syndrome containing said artificial lung surfactant as an active principle.
There exists in alveoli of animal lungs a physiological active substance, which is called a lung surfactant, mainly comprising phospholipid This substance covers the inner walls of the aveoli of the lung to protect the alveolar epitheliums and also performs an important physiological function for animals to maintain their respiratory functioning. More particularly, the lung surfactant is regarded as a substance having a specific surface-active function to change the surface tension of the inner walls of the alveoli of the lung corresponding to the exhalation and inhalation of breath and also contributing to the maintenance of interalveolium functional stability to exercise an antiatelectatic action. After years of research conducted in medical circles with the use of various animals with regard to the lung surfactant, detailed particulars of its activities are now being made clear step by step. It has been made apparent that this active substance contains phospholipids, neutral lipids, protein, etc., as ingredients and that its main constituent is dipalmitoyl lecithin which is known as one of the phospholipids.
T. Fujiwara et al. recently reported that they obtained an artificially prepared lung surfactant having a higher surface activity by adding dipalmitoyl lecithin, etc., to a surfactant recovered from the bovine lung and that they achieved a good result for the therapy of infantile respiratory distress syndrome (IRDS) by the instillation of the said lung surfactant dispersion to the respiratory tracts of premature babies (Pediatric Clinics, Vol. 32, No. 7, p. 1343, 1979).
Also Kobayashi et al. obtained a lung surfactant prepared from an active substance isolated from swine lung washings, in which Ca.sup.++ was made to coexist to enhance the activity, and successfully achieved a good result for the substitution therapy of IRDS (Journal of Japanese Medical Society for Biological Interface Vol. 12, No.1, 1981).
In these methods, it is intended to extract phospholipid only from the natural lung surfactant following the Folch procedure, wherein organic solvent soluble substances are extracted by use of a mixed solvent consisting of chlorform and methanol, eliminating the foreign protein arising from bovine and swine; however, the elimination is incomplete and the intermixture of foreign protein up to about 1 to 3% in the obtained phospholipid is observed. Also, the existence of protein, which is proper to the lung but different from ordinary serum albumin, in the naturally obtained lung surfactant is recognized by King et al. (King S.Am. J. Phyoiol. 224 788.about.795, 1973. Fed. Proc. 33 2238.about.2241, 1974). It is known that this is a liposoluble protein, which is mainly of a molecular weight of 34,000, containing a hydrophobic amino acid in the large quantities. From the facts mentioned in the above, it is considered that in case where a lung surfactant is prepared from lipids extracted from the native lung surfactant according to the Folch procedure, not only desired phospholipid, neutral lipids, etc., but also protein proper to the lung are extracted and the presence of such protein is regarded as inevitable. The existence of such protein in the lung surfactant is not desirable from the medicamental viewpoint, since it give the strong probability of causing the manifestation of antigenecity and side effects including anaphylaxis.
With the purpose of overcoming the abovementioned defects, C. J. Morley et al. attempted the preparation of an artificial lung surfactant containing no foreign protein and succeeded clinically in its application to IRDS (The Lancet, Jan, 10, 1981). However, this artificial surfactant is prepared in the form of a powder containing dipalmitoyl phosphatidyl choline and phosphatidyl glycerol at the weight ratio of 7:3 and its administration is limited to powder administration which presents some technical difficulty in administration to the alveoli.